Objective
The aim of the DIAGNODE-3 phase 3 trial is to confirm the safety and efficacy of three injections of the diabetes vaccine Diamyd® injected into a lymph node regarding the preservation of own insulin production (stimulated C-peptide level) and blood sugar control (HbA1c). The objective is to confirm the beneficial effects of Diamyd® compared to placebo treatment over a 2-year period on top of current standard of care diabetes treatment and is planned to serve as the basis for a future marketing authorisation application.
Background Rationale
The diabetes vaccine Diamyd® is an antigen-specific immunotherapy for the preservation of endogenous insulin production. Significant and clinically meaningful results have been shown in a large genetically predefined patient group in a large-scale meta-analysis as well as in Diamyd Medical's European Phase IIb trial DIAGNODE-2, where the diabetes vaccine was administered directly into a lymph node in children and young adults with recently diagnosed Type 1 Diabetes. The statistically significant and clinically meaningfuls beneficial effects on preservation of own insulin production and blood glucose control are based on over 600 patients in total. Treatment with Diamyd® is safe, with no major safety signals or expected serious adverse events in >1,500 persons enrolled in >15 previous clinical trials of whom >1,000 received active treatment.
Compared to the previous clinical programme with Diamyd® (before 2013) that did not quite achieve its primary objective, two major discoveries and changes in the current clinical development programme have dramatically increased the likehood of success. Firstly, it has been shown that intralymphatic injection of Diamyd® is more effective than subcutaneous injection (used before 2013). Secondly, the responder sub-population for Diamyd® treatment has been identified as the 40% of recently-diagnosed Type 1 Diabetes patients who carry the genetic HLA DR3-DQ2 marker. The active ingredient of Diamyd® is the human GAD protein and it is well established that individuals born with HLA DR3-DQ2 tend to develop autoimmunity foremost against GAD. Apart from the identification of this responder population in the clinical data, this association provides therefore also a biological rationale for why treatment with Diamyd® should be efficacious in individuals with HLA DR3-DQ2. These two discoveries are being implemented in the DIAGNODE-3 phase 3 trial, which assesses intralymphatic administration of Diamyd® in the HLA DR3-DQ2 responder population.
Description of Project
The placebo-controlled Phase III trial DIAGNODE-3 will include approximately 330 individuals aged 12 to 28 who have recently been diagnosed with Type 1 Diabetes and who carry the HLA DR3-DQ2 gene. DIAGNODE-3 aims to confirm the safety and efficacy of the therapeutic diabetes vaccine Diamyd® for the preservation of own insulin production and blood sugar control and has been designed to serve as the basis for potential marketing authorisation. The trial will be conducted at approximately 50 clinics, where almost half of all individuals with recent onset Type 1 Diabetes are estimated to carry the genetic marker required for inclusion into the study. After an initial month in which all trial participants receive vitamin D, the individuals will be randomized 2:1, that is, two out of three trial participants will receive intralymphatic injections of Diamyd® and one in three will receive the corresponding placebo. The assigned treatment will be administered by ultrasound-guided intralymphatic injection at Months 0, 1, 2, and all individuals will be followed for another 22 months (24 months in total). The design provides, based on efficacy data from previous studies with the HLA-restricted patient population, a high probability of reaching the co-primary endpoints of preservation of own insulin production and lower HbA1c. Both of these endpoints are associated with direct benefits for patients. The study treatment is given on top of standard of care diabetes treatment. The Coordinating Investigator for the trial is Professor Johnny Ludvigsson of Linköping University in Sweden. The Sponsor of the trial is the Swedish company Diamyd Medical.
Anticipated Outcome
It is anticipated that three intralymphatic doses of Diamyd® (compared to placebo) will be safe and well tolerated without any major safety signals. It is anticipated that Diamyd® will stop or slow the autoimmune destruction of insulin-producing beta cells which will be reflected in greater preservation of own insulin production compared to placebo treatment after 24 months. Since preservation of own insulin production has been strongly linked to better short-term and long-term outcomes (such as better glucose control and lower risks of diabetes complications), it is expected that individuals treated with Diamyd® will experience significant health benefits and improved quality of life in the future. Apart from the anticipated benefits on preserved insulin production, it is also expected that Diamyd®-treated individuals will have better blood glucose control (HbA1c) after 24 months. Other benefits for reduced incidence of serious diabetes complications (ketoacidosis and hypoglycemia) and glucose control measured by continuous glucose monitoring are also expected to be seen at 24 months. These benefits from Diamyd®-treatment compared to placebo treatment are anticipated on top of standard of care treatment - no patient in the study is denied state-of-the-art diabetes care according to current guidelines.
Relevance to T1D
There is to date no approved disease-modifying treatment that halts or slows the autoimmune destruction of beta cells in patients with Type 1 Diabetes. Confirming the effect and leading to the potential approval of a safe, well-tolerated, short-term (3 monthly injections initially) and clinically efficiacious disease-modifying treatment such as Diamyd® would be an enormous success for the entire field and would benefit not only affected persons and their families but society as a whole, since the anticipated reductions in diabetes complications achieved by Diamyd® would reduce healthcare expenditure spent on the consequences of Type 1 Diabetes tremendously. The treatment is moreoever paradigm-shifting since the established notion of Type 1 Diabetes as a single disease entity with a one-size-fits-all approach is no longer the accepted standard, as demonstrated by a myriad of failed trials targeting the entire Type 1 Diabetes population. The precision-medicine approach taken in the DIAGNODE-3 trial with Diamyd® includes enrolling only those patients who carry the gene that makes them most likely to benefit from Diamyd® treatment. This is the first precision-medicine regitrational Phase 3 trial in Type 1 Diabetes, and its success would have huge implications for informing other therapeutic approach in Type 1 Diabetes that are tailored to the individual. It is also important to stress that the anticipated benefits of Diamyd® come on top of standard of care treatment. That is, no patient is denied current optimized insulin treatment or has to give up part of their guideline-based diabetes treatment.